Triple negative breast cancer (TNBC) is very difficult to treat and has no specific targeted therapies. Chemotherapies used to treat this disease have many undesirable side-effects and patients eventually relapse as a result of chemoresistance. Obesity is pandemic in the US and many TNBC suffer from this as well. Obesity is accompanied by high levels of leptin and is linked to the highest mortality rates in TNBC patients. In contrast to normal mammary cells, TNBC cells overexpress the leptin receptor and significantly proliferate under leptin interactions. Our exciting findings suggest leptin is involved in TNBC acquired drug resistance through the induction of breast cancer stem cells (BCSC). Anti-angiogenic drugs show limited success for TNBC, but these shortcomings could be due in part to angiogenic signal redundancy, i.e., leptin. JYANT Technologies, Inc. has designed a proprietary, potent and highly specific inhibitor of leptin-signaling, leptin peptide receptor antagonist-2 (LPrA2). The peptide conjugated to polyethylene glycol (20 kDa; PEG-wLPrA2) has a 68 hour half-life after intravenous administration and significantly reduces TNBC growth. Preliminary data also show that PEG-wLPrA2 does not induce changes in food intake, body weight or general health status. We propose the use of PEG-wLPrA2 as an adjuvant therapy for TNBC that will improve the efficacy and reduce dosage and toxicities associated with current TNBC therapy (e.g., doxorubicin + cyclophosphamide + paclitaxel). PEG-wLPrA2 will target leptin's proliferative, pro-angiogenic and BCSC related actions in TNBC. This study will evaluate this novel adjuvant therapy in clinically relevant (obesity) TNBC models. Specifically, toxicity an adjuvant therapy studies along with doxorubicin, cyclophosphamide and/or paclitaxel treatments will be carried out in lean and obese mice hosting human and mouse TNBC xenografts and syngeneic grafts. The experimental data generated from this STTR Phase I proposal will allow for the rapid translation of an innovative and targeted adjuvant therapy for TNBC. This novel strategy will generate an effective therapy for reducing chemoresistance, relapse and metastasis of TNBC via depletion BCSC, which are maintained by leptin-signaling. Our proposed studies are of paramount importance for TNBC sufferers, especially those that are overweight or obese, which shows the highest levels of leptin and TNBC incidence.